Although tobacco smoke is the primary risk factor for development of chronic obstructive pulmonary[unreadable] disease (COPD), additional pathologic processes appear to be critical for disease progression. Our[unreadable] previously published findings show the lesions of small airways that define COPD are highly associated[unreadable] with histologic evidence of adaptive immune responses. Recent preliminary observations by our group[unreadable] also show that the severity of COPD is closely correlated with expressions of selected immune and injury[unreadable] response mediators in airways and sera of afflicted patients. Furthermore, peripheral T-cells among these[unreadable] patients exhibit strikingly abnormal activation phenotypes and effector functions that correlate with disease[unreadable] severity. We have also demonstrated a soluble mediator(s), uniquely elaborated by the T-cells from[unreadable] COPD patients, induces marked abnormalities of differentiated human airway epithelial cells. In addition,[unreadable] we have documented the presence of circulating anti-epithelial IgG antibodies in COPD patients, and the[unreadable] pathogenic relevance of this observation is corroborated by findings of IgG deposition within COPD lungs.[unreadable] We hypothesize abnormalities of adaptive immunity play an important role in the pathogenesis of[unreadable] COPD progression.[unreadable] The investigations proposed in this Project will further define the nature and role of these injurious[unreadable] processes. The antigen specificity of the T-cells that incite and sustain these responses will be confirmed[unreadable] by findings of clonal proliferations proximate to diseased small airways. Additional correlative immune[unreadable] and injury gene expressions in situ from among lesions of varying severity will identify and confirm[unreadable] important pathogenic mechanisms of COPD progression. The mediators elaborated by COPD T-cells that[unreadable] directly injure airway epithelium will be identified with a unique in vitro model, using cellular materials[unreadable] derived from COPD lungs. Detailed characteristics of the autoantibody productions in COPD patients will[unreadable] be further defined, and correlates with clinical and T-cell functions will be established. These interrelated[unreadable] investigations will further our basic understandings of COPD pathogenesis, and will likely illustrate cellular[unreadable] subpopulations and mechanisms that may be amenable to novel therapeutic interventions.